Exciting advances over recent years have identified specific pathways in the brain that become overactive in patients with Parkinson’s disease. The primary pathology of Parkinson’s disease involves death of specific neurons in the brain containing the neurotransmitter dopamine. However, the loss of these dopamine neurons leads to pathological increases in activity of other neurons that remain intact in Parkinson’s patients.
This understanding has led to major breakthroughs in developing surgical strategies for treatment of Parkinson’s disease aimed at reducing the excessive activity through these brain pathways. These surgical procedures provide a major benefit to patients who receive them. However, because of the high risk and high level of expertise required for performing these surgeries, these procedures are not available to many Parkinson’s patients.
Because of this, we have focused a major effort on developing strategies for reducing activity through these pathways using drugs rather than surgical techniques. If successful, this would allow wide use of this strategy in a broad range of Parkinson’s patients who are not effectively treated or who experience serious adverse responses to currently available antiparkinsonian medications. Also, recent studies suggest that this strategy may be effective in slowing progression of Parkinson’s disease when administered to patients early in the course of the disease. We have identified a novel neurotransmitter receptor known as mGluR7 that reduces activity of this critical neuronal pathway when activated.
The goal of this project was to identify compounds that could activate/potentiate mGluR7 function. The researchers found that complexities exhibited by different types of compounds, as well as differences in activities among various cellular backgrounds, suggest that the pharmacology of mGluR7 activators/potentiators appears to be context-dependent and may be driven by protein-protein interactions or other signaling events. These factors will play an important role in the development of techniques to search for new compounds to manipulate receptor function, as well as the in vitro methods used to characterize identified compounds. Further exploration is needed to more completely define the intricacies of regulation of this receptor.
Results of this project were published in Neuropharmacology,
Proceedings of the National Academy of Sciences, Molecular Pharmacology and the Journal of Pharmacology and Experimental Therapeutics.